The development of fibrous delivery systems for delivery of bioactive agents at controlled rates to specific body sites has been established for a variety of applications. However, each application presents unique problems both with respect to forming the fiber, combining the fiber with the agent whether in monolithic, coaxial or hollow fiber form and establishing those characteristics necessary to control release of the agent at some desired rate. While the desirable characteristics of povidone-iodine have been known for some time, the povidone-iodine complex had never to the best of applicant' knowledge been successfully incorporated into a fibrous delivery system prior to the invention described herein.
Povidone-iodine is a complex of poly(vinylpyrrolidone) and iodine. Poly(vinylpyrrolidone) (PVP) is produced by the free-radical polymerization of N-vinyl pyrrolidone. The polymer is water soluble even at high molecular weights and is physiologically acceptable to both animals and humans with uses as a plasma volume expander, drug vehicle, and as a suspending agent because of its protective colloid effect. Poly(vinylpyrrolidone) has also been added to fiber-forming polymers to give improvements in dye receptivity. Many of these polymer mixtures were melt spun.
Iodine is strongly complexed by PVP. Apparently, part of the iodine (about 30%) is converted to iodide which organically binds to the polymer. This bound iodide then stabilizes the remaining iodine in the same manner as potassium iodide in solution. The free iodine appears to be in solution in the PVP-iodide compound. In this complex, the vapor pressure of the free iodine is reduced essentially to zero resulting in a more stable microbiocide. The release of the available iodine at a slow rate from the complex when it is dissolved in water prolongs the microbiocidal action of the free iodine.
Iodine is recognized as a non-selective microbiocide which kills microorganisms immediately in tissue. Iodine has also been found to possess both fungicidal and viricidal properties. However, free iodine presents several difficulties in clinical use. The problems include oral toxicity, tissue irritation, and staining. The PVP-iodine complex minimizes most of these problems with reduced oral toxicity, almost no irritation to tissues, and no stains as a result of its water solubility.
Povidone-iodine has given excellent microbiocidal effects in surgical scrub, surgical preparation, and treatment of wounds, burns, and vaginal infections. Of particular interest, povidone-iodine is now frequently used as a douche or gel for treatment of vaginitis and vaginal trichomoniasis. In these applications, povidone-iodine affords several advantages in that it is non-staining, effective on a broad spectrum of bacteria, and does not appear to cause the formation of strain-resistant microorganisms as do the antibiotics. It would thus be desirable to incorporate povidone-iodine into a fiber.
As to other drug fiber technology, it will be noted that U.S. Pat. No. 3,926,188 to Baker et al discloses a polymeric drug dispenser which may be composed of polyethylene and may be inserted into body cavities, such as the vagina. U.S. Pat. No. 3,875,300 to Homm et al discloses intravaginal inserts which are composed of biodegradable polymers blended with medicaments in the form of fibers. U.S. Pat. No. 3,880,991 to Yolles is also noted as disclosing polymeric articles for dispensing drugs which may take the form of intrauterine devices. U.S. Pat. No. 3,991,766 to Schmitt et al and U.S. Pat. No. 4,118,470 to Casey et al are also noted as disclosing polymeric articles for dispensing drugs and formed into the shape of a thread, suture, ligature, or the like, for the controlled in vivo, continuous administration of a predetermined dosage of a drug to a living animal. U.S. Pat. No. 3,279,996 to Long, Jr. et al is noted as disclosing a drug enclosed in a silicone rubber capsule adapted for implantation and diffusion of the drug into the tissue of a living organism.
U.S. Pat. No. 3,896,819 to Zaffaroni teaches a drug dispensing device comprising a liquid mass of a low molecular weight drug compound enclosed by a wall. The Zaffaroni liquid reservoir system exhibits zero order release kinetics as contrasted to the first order or psuedo zero-order release kinetics of the present invention. Zaffaroni makes no reference to use of a high molecular weight polymer complex such as the povidone-iodine complex of the present invention. U.S. Pat. No. 3,921,636 to Zaffaroni teaches a drug dispensing device comprising a plurality of capsule like reservoirs containing drugs distributed through a matrix. The drug release rate from the reservoir walls is lower than that of the surrounding matrix material. Zaffaroni U.S. Pat. No. '636 also teaches forming the reservoirs in a matrix which assumes a fiber form. However, the Zaffaroni U.S. Pat. No. '636 system makes no reference to the use of or how to use the povidone-iodine complex of the present invention either in embedded reservoirs or otherwise. Also to be noted is U.S. Pat. No. 4,024,871 to Stephenson which teaches a multi-filament suture with several strands in which an antimicrobial is trapped within the interstices of the filaments without penetrating the fibers themselves.
With the above background art in mind, it is noted that the art has not disclosed povidone-iodine-loaded polymer fibers generally or specifically for intravaginal inserts. Neither has the art provided polyethylene fibers loaded with povidone-iodine and in a form adapted to provide a controlled, sustained release especially for intravaginal insert applications.
The general object of the invention is thus that of providing povidone-iodine loaded fibrous polymers specifically contemplated for use in the in vivo delivery of the povidone-iodine to humans and more specifically as an intravaginal implant. Even more specifically an object of the invention is to achieve this result with the fibrous polymer loaded with povidone-iodine in a thread-like form suited, for example, as the tail or pull string for an intrauterine device.